In 1950, the CIA initiated Project Bluebird, later renamed Project Artichoke, whose stated purpose was to develop "the means to control individuals through special interrogation techniques", "way[s] to prevent the extraction of information from CIA agents", and "offensive uses of unconventional techniques, such as hypnosis and drugs". The purpose of the project was outlined in a memo dated January 1952 that stated, "Can we get control of an individual to the point where he will do our bidding against his will and even against fundamental laws of nature, such as self preservation?" The project studied the use of hypnosis, forced morphine addiction and subsequent forced withdrawal, and the use of other chemicals, among other methods, to produce amnesia and other vulnerable states in subjects. In order to "perfect techniques for the abstraction of information from individuals, whether willing or not", Project Bluebird researchers experimented with a wide variety of psychoactive substances, including LSD, heroin, marijuana, cocaine, PCP, mescaline, and ether. Project Bluebird researchers dosed over 7,000 U.S. military personnel with LSD, without their knowledge or consent, at the Edgewood Arsenal in Maryland. More than 1,000 of these soldiers suffered from several psychiatric illnesses, including depression and epilepsy, as a result of the tests. Many of them tried to commit suicide.

In 1953, the CIA placed several of its interrogation and mind-control programs under the direction of a single program, known by the code name MKULTRA, after CIA director Allen Dulles complained about not having enough "human guinea pigs to try these extraordinary techniques". The MKULTRA project was under the direct command of Dr. Sidney Gottlieb of the Technical Services Division. The project received over $25 million, and involved hundreds of experiments on human subjects at eighty different institutions.

In a memo describing the purpose of one MKULTRA program subprogram, Richard Helms said: We intend to investigate the development of a chemical material which causes a reversible, nontoxic aberrant mental state, the specific nature of which can be reasonably well predicted for each individual. This material could potentially aid in discrediting individuals, eliciting information, and implanting suggestions and other forms of mental control. —Richard Helms, internal CIA memo

In 1954, the CIA's Project QKHILLTOP was created to study Chinese brainwashing techniques, and to develop effective methods of interrogation. Most of the early studies are believed to have been performed by the Cornell University Medical School's human ecology study programs, under the direction of Dr. Harold Wolff. Wolff requested that the CIA provide him any information they could find regarding "threats, coercion, imprisonment, deprivation, humiliation, torture, 'brainwashing', 'black psychiatry', and hypnosis, or any combination of these, with or without chemical agents". According to Wolff, the research team would then: ...assemble, collate, analyze and assimilate this information and will then undertake experimental investigations designed to develop new techniques of offensive/defensive intelligence use ... Potentially useful secret drugs (and various brain damaging procedures) will be similarly tested in order to ascertain the fundamental effect upon human brain function and upon the subject's mood ... Where any of the studies involve potential harm of the subject, we expect the Agency to make available suitable subjects and a proper place for the performance of the necessary experiments. —Dr. Harold Wolff, Cornell University Medical School

Another of the MKULTRA subprojects, Operation Midnight Climax, consisted of a web of CIA-run safehouses in San Francisco, Marin, and New York which were established in order to study the effects of LSD on unconsenting individuals. Prostitutes on the CIA payroll were instructed to lure clients back to the safehouses, where they were surreptitiously plied with a wide range of substances, including LSD, and monitored behind one-way glass. Several significant operational techniques were developed in this theater, including extensive research into sexual blackmail, surveillance technology, and the possible use of mind-altering drugs in field operations.